The invention disclosed herein is directed to certain substituted azacycles useful as tachykinin receptor antagonists. In particular, the compounds disclosed herein are neurokinin receptor antagonists.
The tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), are structurally similar members of a family of neuropeptides. Each of these is an agonist of the receptor types, neurokinin-1 receptor (NK-1), neuorokinin-2 receptor (NK-2) and neuorokinin-3 receptor (NK-3), which are so defined according to their relative abilities to bind tachykinins with high affinity and to be activated by the natural agonists SP, NKA and NKB respectively.
The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2. More specifically, substance P is a pharmacologically-active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence:
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2 PA1 Neurokinin A possesses the following amino acid sequence: PA1 Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2. PA1 (Chang et al., Nature New Biol. 232, 86 (1971); D. F. Veber et al., U.S. Pat. No. 4,680,283). PA1 R.sub.3 is H, methyl or ethyl. PA1 R.sub.2 is
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2. PA2 (b) --N(R.sub.3)C.sub.1-4 alkylphenyl, wherein the C.sub.1-4 alkyl may be linear or branched, the phenyl is optionally mono di or trisubstituted and wherein the substitutents are independently halo, methyl, methoxy or CF.sub.3 and n is 1, or 2; PA2 (a) --OCH.sub.2 phenyl, wherein the phenyl is optionally mono di or trisubstituted phenyl wherein the substitutents are independently halo, methyl, methoxy or CF.sub.3 ; PA2 (b) --NHCH.sub.2 phenyl, wherein the phenyl is optionally mono di or trisubstituted phenyl wherein the substitutents are independently halo, methyl, methoxy or CF.sub.3 ; PA2 (c) --N(CH.sub.3)CH.sub.2 phenyl, wherein the phenyl is optionally mono di or trisubstituted phenyl wherein the substitutents are independently halo, methyl, methoxy or CF.sub.3 ; PA2 (d) --N(CH.sub.3)CH(CH.sub.3)phenyl, wherein the phenyl is optionally mono di or trisubstituted phenyl wherein the substitutents are independently halo, methyl, methoxy or CF.sub.3 ; and PA2 (f) --N(CH.sub.3)CH(CH.sub.2 CH.sub.3)phenyl, wherein the phenyl is optionally mono di or trisubstituted phenyl wherein the substitutents are independently halo, methyl, methoxy or CF.sub.3.
Neurokinin B possesses the following amino acid sequence:
The neurokinin receptors are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK1 and NK2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42: 1295-1305 (1988)).
Substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (198 1)). In particular, substance P has been shown to be involved in the transmission of pain in migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226, 547-549).
In the airways, it has been indicated that NK1 receptors are associated with microvascular leakage and mucus secretion, while NK2 receptors regulate smooth muscle contraction. Also, it has been shown that both substance P and neurokinin A are effective in inducing airway constriction and edema. Based on such findings, it is believed that substance P and neurokinin A may be involved in the pathogenesis of neurogenic inflammation, including allergic diseases such as asthma. (Frossard et al, Life Sci., 49, 1941-1953 (1991); Advenier, et al, Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).
In experimental studies, sensory neuropeptides, especially tachykinins such as substance P and neurokinin A, can bring about many of the pathophysiological features of asthma. Neurokinin A is a very potent constrictor of human airways in vitro, and substance P causes mucus secretion in the airways. (Barnes P. J., Lancet, pp 242-44 (1986); Rogers D. R., Aursudkij B., Barnes P. J., Euro. J. Pharmacol, 174, 283-86 (1989)).
Inhalation of bradykinin causes bronchoconstriction in asthmatic patients but not in normal subjects. (Fuller R. W., Dixon C. M. S., Cuss F. M. C., Barnes P. J., Am Rev Respir Dis, 135, 176-80 (1987)). Since the bradykinin-induced bronchoconstriction is partly opposed by anticholinergic agents and since bradykinin is only a weak constrictor of human airways in vitro, it has been suggested that the bronchoconstrictor response is partly mediated by a neural reflex. Bradykinin stimulates vagal afferent C fibers and causes broncho-constriction in dogs. (Kaufman M. P., Coleridge H. M., Coleridge J. C. G., Baker D. G., J. Appl. Physio., 48, 511-17 (1980)). In guinea-pig airways, bradykinin causes a bronchoconstrictor response by way of cholinergic and sensory-nerve-mediated mechanisms. (Ichinoe M., Belvisi M. G., Barnes P. J., J. Pharmacol. Exp. Ther., 253, 594-99 (1990). Bradykinin-induced bronchoconstriction in human airways may therefore be due partly to tachykinin released from sensory nerve terminals via axon reflex mechanisms. Clinical trials have shown that a dual NK-1/NK-2 antagonist (such as FK-224) protects against bradykinin induced bronchocontriction in asthmatic patients. (Ichinoe, M. et al., Lancet, vol. 340, pp 1248-1251 (1992)).
The tachykinins have also been implicated in gastro-intestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al., Neuroscience, 25 (3), 817-37 (1988) and D. Regoli in "Trends in Cluster Headache" Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
It is also hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al., "A Neurogenic Mechanism for Symmetric Arthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al., "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10). Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., in Arthritis and Rheumatism (1990) 33, 1023-8). Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et al, Can. J. Pharmacol. Physiol. (1988) 66, 1361-7), immunoregulation (Lotz et al., Science (1988) 241, 1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9 and A. Perianin, et al., Biochem. Biophys. Res. Commun. 161, 520 (1989)) vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh et al., PNAS (1988) 85, 3235-9) and, possibly by arresting or slowing .beta.-amyloid-mediated neurodegenerative changes (Yankner et al, Science, (1990) 250, 279-82) in senile dementia of the Alzheimer type, Alzheimer's disease and Downs Syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (J. Luber-Narod et al., poster presented at C.I.N.P. XVIIIth Congress, 28th Jun. -2nd Jul., 1992). Antagonists selective for the substance P and/or the neurokinin A receptor may be useful in the treatment of asthmatic disease (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).